Method identifies cancer cells that are "primed" to die

Anthony Letai, MD, PhD

A test developed by Dana-Farber Cancer Institute scientists is the
first to identify which malignant blood cells are highly vulnerable to a
promising type of experimental drugs that unleash pent-up "cell
suicide" factors to destroy the cancer.

The researchers demonstrated that chronic lymphocytic leukemia, CLL,
which is diagnosed in 10,000 Americans each year, is an easy mark for
the new drug because the cancerous cells are strongly dependent on a
particular survival molecule, Bcl-2, that keeps the self-destruct
signals at bay. They showed that the investigational drug neutralizes
the Bcl-2 action, unleashing molecules that trigger suicide in the
cancer cells, a process known as programmed cell death or apoptosis.

The research in the laboratory of Anthony Letai, MD, PhD, of Dana-Farber, is described in the January issue of The Journal of Clinical Investigation. The lead author is Victoria Del Gaizo Moore, PhD, a member of the Letai group.

Letai was a colleague of the late Stanley J. Korsmeyer, MD, of
Dana-Farber, who discovered the key role in cancer played by
anti-apoptosis molecules such as Bcl-2, which promote the survival of
cells that are damaged or abnormal despite the body's efforts to
eliminate them through apoptosis.

Inspired by this pioneering research, drug companies have begun
testing novel Bcl-2 inhibiting drugs designed to restart the natural
death processes thwarted by the survival molecule.

Letai said that his group has tested Abbott's investigational
compound ABT-737 against cultured CLL cells with striking results.
"We've treated CLL samples from several dozen patients, and each has
responded to a very low concentration of the drug," said Letai. "We find
it particularly interesting that the cells died within four hours."

Cells from CLL, a currently incurable disease, are vulnerable to this
dramatic reversal of fortune because they are "primed for death;" they
are surviving only because Bcl-2 proteins are blocking powerful
cell-death molecular signals by holding them hostage. Primed cells,
Letai explained, are like a car with a revved-up engine on the edge of a
cliff, restrained only by its emergency brake; if the brake was
released, the car would plunge over the cliff.

Drugs such as ABT-737, in effect, release the brake. The drug
molecules liberate the pro-death signaling molecules from their Bcl-2
captors. These pro-apoptosis molecules – a key one is called BIM – then
trigger a chain of events that cause the cell's power plants, or
mitochondria, to rupture and spill out chemicals that cause the cell to
die and be tagged for disposal. This class of drugs is expected to be
relatively non-toxic to most normal cells, which are much less dependent
on Bcl-2 function than are cancer cells to stay alive.

"It's essential to figure out which cancers are going to respond to
the drug by identifying the cells that are dependent on Bcl-2 for
survival," said Letai, who is also an assistant professor of medicine at
Harvard Medical School. "Up to now there hasn't been a way to do this."

In developing the test, the Letai team first isolated mitochondria
from cancer cells; then they exposed them to protein fragments –
peptides – that were known to interact with survival molecules like
Bcl-2. "If they interact, then the cell is primed to die, and the test
will identify which of the survival molecules is keeping the cells
alive," he added. "Then you know that to kill the cell, you have to
target Bcl-2."

The researchers have dubbed the test "BH3 profiling" because the
array of protein fragments are known as "BH3 domains." Letai said work
is under way to make the laboratory profiling operation more automated,
looking toward a time when it could be used on a routine basis to assess
the vulnerability of patients' cancers to compounds that antagonize
BCL-2 or related anti-death proteins.

"This is a totally new class of drugs and has the potential to be a major addition to how we treat cancer," he said.

The research was funded by the National Institutes of Health, the
Dunkin Donuts Rising Stars Program, the Richard and Susan Smith Family
Foundation, and the Sidney Kimmel Foundation for Cancer Research.

Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National
Cancer Institute.